tbuckley/cabot-search huggingface dataset:
Assessment of efficacy and safety of dose-dense doxorubicin and cyclophosphamide (ddAC) in combination with pembrolizumab in early-stage, triple-negative breast cancer.
Authors: Olivia White, Susan Faye Dent, Kelly E. Westbrook, Heather Moore
Journal: Journal of Clinical Oncology (2023)

e12618 Background: KEYNOTE-522 demonstrated significant improvement in pathologic complete response (pCR) and event free survival (EFS) for early stage triple negative breast cancer (TNBC) patients (pts) treated with pembrolizumab (PEMBRO) and chemotherapy (carboplatin/paclitaxel weekly followed by doxorubicin/cyclophosamide (AC) every 3 weeks) in the neo/adjuvant setting. Standard of care prior to KEYNOTE-522 was AC every 2 weeks (dd), however, implementation of ddAC becomes impractical when accommodating 21-day PEMBRO dosing and creates concern for compromised efficacy. KEYNOTE-555 demonstrated feasibility of every 6-week PEMBRO dosing. We modified the KEYNOTE-522 regimen to employ ddAC with PEMBRO every 6-weeks with the aim to maximize clinical outcomes while reducing time spent in the infusion center. The primary objective is to compare the rate of pCR using ddAC plus 6-week PEMBRO versus PEMBRO and AC every 3 weeks. Secondary objectives include: safety of concomitant chemoimmunotherapy by comparing the incidence of adverse events (AEs) with PEMBRO (every 3 or 6 weeks), assessing rates of held cycles or dose modifications, and assessing toxicity of concomitant capecitabine and PEMBRO in the adjuvant setting. Methods: This was a retrospective, single-center, cohort study at Duke University Hospital (DUH). Results reported via descriptive statistics. Adult pts with clinical stages I-III TNBC were included in this study. Pts must have completed four cycles of AC. Pre-specified data collection points were obtained from the electronic health record and entered into a secure database. Results: A total of 25 female pts treated at DUH were included. The rate of pCR was 64.3% (AC) versus 81.8% (ddAC). All patients experienced at least one adverse event with their immunochemotherapeutic regimen. The most common IO-induced toxicities included thyroid-associated AEs (37.5%) and rash (37.5%). There were no grade 3 or 4 IO-induced toxicities reported. Five patients were on concomitant adjuvant capecitabine and PEMBRO for residual disease. One patient in each arm required dose adjustments for capecitabine and 3 patients had at least one deferred cycle. One patient experienced AEs associated with capecitabine. No patients had toxicities attributable to adjuvant PEMBRO. Conclusions: In this small single center study, the administration of neoadjuvant ddAC with PEMBRO at 400mg every 6 weeks was deemed feasible with no excess toxicity. There was a trend towards improved efficacy for patients treated with ddAC with PEMBRO. Additionally, safety endpoints were similar between groups. This dosing strategy allows for optimization of therapy with the incorporation of ddAC and adjuvant capecitabine, thus potentially improving outcomes in TNBC patients. Larger cohort studies, in the real-world setting, are needed to confirm these findings.
Cardiac safety and efficacy for patients with early-stage breast cancer treated with pegylated liposomal doxorubicin (PLD) or doxorubicin.
Authors: Lichen Tang, Min He, Jiong Wu, Zhonghua Wang, Guangyu Liu, Keda Yu, Cuizhi Geng, Zhimin Fan, Rui Ling, Guangdong Qiao, Li Cai, Ting Luo, Feng Jin, Haibo Wang, Anqin Zhang, Hongwei Zhang, Xiaohua Zeng, Xiaojia Wang, Ming Jiang, Shao Zhimin
Journal: Journal of Clinical Oncology (2023)

550 Background: Anthracyclines play an important role in the treatment of breast cancer (BC) while cardiotoxicity, a serious side effect, limits the clinical application. Pegylated liposomal doxorubicin (PLD) is a new dosage form of doxorubicin encapsulated in liposomes, which can reduce the plasma free level of doxorubicin and drug to normal tissue delivery, thereby reducing cardiotoxicity. The aim of this study was to evaluate the cardiac safety and efficacy of PLD compared with doxorubicin as adjuvant therapy in breast cancer patients. Methods: This is an open-label, randomized trial involving patients with operable breast cancer who were at high risk of recurrence after radical sugery (NCT03949634). Patients were randomized (1:1) to receive adjuvant PLD or doxorubicin (A) and cyclophosphamide followed by taxanes ± trastuzumab. The primary endpoint was cardiotoxicity, which was defined as congestive heart failure (CHF) with clinical symptoms, or no symptoms but with an abnormal left ventricular ejection fraction (LVEF). Secondary endpoints included 5-year disease-free survival (DFS) rate, 5-year overall survival (OS) rate and safety. Results: Between November 2017 and September 2019, 247 patients were randomized and received study treatment (PLD arm, 131; A arm, 116). The median age was 49 years (range, 26-67) in PLD arm and 48 years (range, 25-70) in A arm. The pathological stages were 18.3% stage I, 58.0% stage II, and 22.1% stage III in PLD arm, while those of A arm were 20.7% stage I, 59.5% stage II, and 19.8% stage III. The median follow-up time was 43.0 months. The incidence of abnormal LVEF was 0 in the PLD arm and 1.7% the A arm (P = 0.220). The incidence of CHF was 0 in the PLD arm and 0.9% the A arm (P = 0.470). Survival data analysis is immature. The exploratory analysis of cardiac-related biomarkers showed that the incidence of high-sensitivity cardiac troponin-T (hs-cTnT) was lower in PLD arm than in A arm (3.8% vs. 30.2%, P &lt; 0.001). Grade 3/4 adverse events (AEs) occurred in 42.7% patients in PLD arm and in 61.2% patients in A arm. The most common grade 3/4 AEs in PLD arm and A arm included neutropenia (34.4% vs. 55.2%), leukopenia (30.5% vs. 39.7%), and hand-foot syndrome (4.6% vs. 0.0%). Conclusions: Hs-cTnT elevation may have a role in the AE prediction of antharcycline. PLD usage may present lower incidence of cardiotoxicity than doxorubicin in the adjuvant treatment of patients with early-stage breast cancer. Clinical trial information: NCT03949634 .
Pulsed electrical fields in combination with anti-PD1 and survival of mice with TNBC (EMT6) murine breast tumor.
Authors: Ebtesam Nafie, Chiara Pastori, Mukta Wagh, Fatima Murad, Mohit Trikha, Robert Neal
Journal: Journal of Clinical Oncology (2023)

540 Background: Delivery of pulsed electric field (PEF) energy is used to destabilize cells through multiple biochemical processes. We questioned whether a specific PEF treatment type could synergize with anti-PD1 in an orthotopic Triple Negative Breast Cancer (TNBC) EMT6 mouse model. Our previous studies have demonstrated that PEF treatment induces neo-antigen presentation and triggers an innate and adaptive immune response. Anti-PD1 therapy is ineffective at blocking growth of (TNBC) EMT6 tumors that are orthotopically implanted in mice. We evaluated whether a biphasic monopolar form of PEF could synergize with anti-PD1 when it was administered intraperitoneally or intra-tumorally, and whether there was a change in immune response post treatment. Methods: Forty-eight female Balb/c mice were implanted with 200,000 EMT6 cells into the mammary fat pads. Once tumor diameter reached 5 mm they were randomized into 6 groups of 8 animals: 1) Sham/IgG; 2) intra-tumoral (IT) anti-PD-1; 3) intra-peritoneal (IP) anti-PD-1; 4) PEF + anti-PD-1(IP); 5) PEF + anti-PD-1(IT) 6) 2X PEF on day 0 and day 7 + anti-PD-1(IT administered weekly). Sham-PEF mimicked the same procedure but without PEF. Anti-PD1 was administered weekly, IT or IP at 200 µg/mouse and PEF was delivered once on day of randomization. Tumors were measured three times per week, and animal survival was monitored until tumor volume necessitated euthanasia (≥2000mm 3 ). Blood was collected on day 14 for flow cytometric analysis of systemic immune response which included quantifying CD3 positive T cells, B cells and NK cells. Results: Anti-PD1 treatment (IT or IP) did not reduce tumor growth, nor did it prolong survival compared to Sham/IgG treated animals. All anti-PD1 alone (IT or IP) as well as Sham treated animals had to be euthanized by day 35. In contrast, PEF combined with anti-PD1 given IT and IP significantly reduced tumor growth by 83% and 70%, respectively, on Day 14 compared to anti-PD-1 only treated animals (p = 0.03). Interestingly, EMT6 bearing mice treated with double PEF + IT administered anti-PD1 survived longer compared to mice treated with single PEF + IT administered anti-PD1. On day 65, 71% of double PEF + IT administered anti-PD1 were still alive compared to 12.5% of mice treated with PEF + IT administered anti-PD1 (p = 0.002). Flow cytometry analysis on day 14 indicated an increase in circulating adaptive (T- and B-cells) and innate (NK cells) immunocytes in the PEF + anti-PD1 treated animals compared to the control. Conclusions: Collectively, these results indicate that some types of PEF ablation synergize with weekly anti-PD1 in stimulating an increase of CD3+ T cells, B cells and NK cells, reducing tumor growth and prolonging survival of tumor bearing mice. These results suggest the synergistic potential of combining Immunotherapy with some forms of PEF, which warrants further study in patients.
Treatment patterns and clinical outcomes following endocrine resistance among with HER2-low metastatic breast cancer: Retrospective observational study.
Authors: Sandhya Mehta, Kristin M. Zimmerman Savill, Peng Wang, Prathamesh Pathak, Clara Lam, Jackie Kwong, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2023)

e13069 Background: Endocrine therapy (ET) ± CDK 4/6 inhibitors is a common initial treatment for HR+/HER2-low (IHC 1+ or IHC2+/ISH-) metastatic breast cancer (mBC). However, many patients eventually progress on ET-based regimen and receive subsequent chemotherapy (CT). This study aimed to describe treatment patterns and outcomes following endocrine resistance among HR+/HER2-low mBC patients in U.S community oncology practices. Methods: Participating oncologists from Cardinal Health’s Oncology Provider Extended Network (OPEN) provided data from the medical charts of adult patients with HR+/HER2-low mBC who received at least two lines (2L) of systemic therapy, with first line (1L) initiated between Feb 19, 2016, and Dec 31, 2018. Analysis was performed among patients who received a subsequent chemotherapy (CT) after progression on their last observed line of ET-based regimen. Patient characteristics and treatment history were summarized descriptively. Kaplan-Meier analyses of treatment outcomes, including physician-reported real-world progression free survival (rwPFS), time to treatment response (TTR) and time to treatment discontinuation (TTD) were performed. Results: 150 HR+/HER2-low mBC patients who received subsequent chemotherapy after ET resistance were included [mean age: 61±11 years, 57.3% were white and 32.7% were black]. The proportion of patients who stopped ET after 1L, 2L and ≥3L of ET were 23.3% (n=35), 70.7% (n=106) and 6.0% (n=9), respectively. The mean duration of ET-based regimens was 29.7 (SD: 13.12) months. Among patients who stopped ET after 1L (n=35), most patients received fulvestrant + palbociclib (48.6%) in 1L prior to switching to CT. Among those who stopped ET after 2 or more lines (n=115), most patients received letrozole + palbociclib (57.4%) in 1L and fulvestrant (46.1%) in 2L. The most common CT regimen utilized was capecitabine (47.0%) followed by paclitaxel (28.0%). The median rwPFS on CT was 8.12 months (95% CI 7.36-9.24), with slightly shorter median rwPFS among those who stopped ET after 1L (7.82 months, 95% CI 7.07-9.53) vs. 2L+ (8.19 months, 95% CI 6.97-9.99). The median TTD of CT was 7.82 months (95% CI 7.07-8.61) and TTR was 4.96 months (95% CI 4.24-5.72), with similar estimates observed between patients who stopped ET after 1L and 2L+. Conclusions: In this small sample of HR+/HER2-low mBC patients, most patients switched to CT after receiving two lines of ET based regimens. Following ET resistance, durability of response with subsequent CT was short and similar irrespective of number of prior lines of ET based regimens. This preliminary chart review study highlights the unmet need for a more effective therapeutic alternative to CT after ET for HR+/HER2-low mBC patients. Further research using larger sample and more robust clinical data is warranted to confirm the study findings.
Evolution of genomic profiles in primary and recurrent brain gliomas.
Authors: Libuse Lizcova, Denisa Vidlakova, Halka Lhotska, Karla Svobodova, Lucie Hodanova, Hana Cechova, Tatiana Aghova, Sarka Ransdorfova, Lenka Pavlistova, David Netuka, Petr Hrabal, Filip Kramar, Zuzana Zemanova
Journal: Journal of Clinical Oncology (2023)

e14042 Background: Diffuse gliomas are highly heterogenous tumors with variable biological behaviors, including high intratumor and extratumor heterogeneity, and with occurrence of recurrent lesions in majority of patients. During disease progression, gliomas undergo cellular and genomic evolution with newly acquired genetic properties. However, the mechanism of this complicated process associated with treatment failure is poorly understood. In this retrospective study, we performed cytogenomic analyses of primary and recurrent tumors in five patients with diffuse glioma who underwent surgical resections or biopsies of multiple recurrences. Methods: One primary and at least two recurrent freshly resected tumor tissues from each patient were analyzed using combination of cytogenomic methods. To assess specific and random copy number alterations (CNAs), I-FISH (Abbott Molecular, MetaSystems), array CGH/SNP (Agilent) and MLPA (MRC Holland) were performed. Methylation of MGMT promoter was investigated by methylation-specific MLPA (MRC Holland) and mutations of 67 genes associated with solid tumors were assessed by target NGS (Archer VariantPlex Solid Tumor, Invitae). Results: All five patients (three men and two women) experienced recurrence with newly acquired genetic or epigenetic changes. We observed a higher frequency of CNAs in recurrent gliomas than in primary tumors. Moreover, several aberrations were not detected in recurrence despite being found in earlier samples. As a primary event we proved mutation R132H of IDH1 gene. In addition, we detected methylation of the MGMT promoter, CDKN2A/B homozygous deletion, and RB1 deletion as later events that were probably associated with higher tumor grades. Besides the typical genomic changes, we detected many aberrations with unknown or unclear prognostic relevance (e.g. inframe deletion in TP53, p.Met243_Asn247del, etc.). The progression to a higher grade of glioma occurred in four patients. Conclusions: The evolutional patterns in glioma depend on clonal selection caused by CNAs, mutations, genetic drift, intratumor heterogeneity and/or the patient’s treatment. Recurrence may arise from one major tumor clone or from one or more subclones within the primary tumor through. Integrated cytogenomic analyses of genetic/epigenetic profiles of primary and all recurrent tissues can contribute to a better understanding of mechanisms responsible for these processes and to identification of new alterations related to gliomas progression and/or resistance to treatment. These biomarkers could subsequently serve as new therapeutic targets for personalized treatment.
Barriers in the identification and diagnosis of hereditary colon cancer.
Authors: Benjamin Usry, Kevin Graf, Rohith Raman, Caitlin Allen, Kiersten Meeder, Kevin S. Hughes, Colleen Donahue
Journal: Journal of Clinical Oncology (2023)

e13524 Background: Lynch Syndrome (LS), the most common form of hereditary colorectal cancer (CRC), is due to germline pathogenic variant (PV) in mismatch repair genes (MMR). Since 2009, the National Comprehensive Cancer Network (NCCN) recommends MMR screening for LS for all CRCs regardless of age. The American College of Medical Genetics and Genomics recommends patients with MMR deficiency or microsatellite instability (MSI) be referred for genetic testing. Despite these recommendations, compliance is low. The aim of this study was to evaluate compliance with LS screening and genetic testing in CRC. Methods: A single institution retrospective review of patients diagnosed with CRC from 2018-2021 was performed. A chart review of those diagnosed in 2018 and 2021 was analyzed and combined as a single population from pre and post COVID periods. A student’s T-Test was used to compare continuous variables and chi square for categorical variables within the two populations. The compliance with either MSI or MMR screening was calculated. Meeting criteria for genetic testing was defined as age less than 50, MSI-L/H or MMR deficient. These patients were then analyzed to determine the proportion of genetic referrals, genetic counseling, genetic testing and identification of LS. Results: 276 patients with CRC were reviewed, 153 in 2018, 123 in 2021. 71.2% were Caucasian and 58% male. There was no statistically significant difference in gender, race or ethnicity, however, there was a difference in age, with a younger average age in 2021 (67, 63; p = 0.014). 146 (53%) patients were screened for LS. 44 (16%) with MSI, 19 (7%) MMR and 82 (30%) with both. 78 patients met criteria for genetic testing; 47 due to age alone, 6 age and positive LS screening and 25 screening alone. 35% (27/78) of those meeting criteria were referred to genetics, of which 63% (17/27) completed their appointment, 63% (17/27) were tested, and 37% (10/27) had a PV identified. Conclusions: Despite guidelines for LS screening, compliance is low with only half of CRC patients appropriately screened at our institution. Even patients with positive screening and those less than 50 were not referred for genetic testing. However, of referred patients, 63% completed their appointment and all those were tested. This supports the idea that poor compliance with genetic testing is not due to patient compliance, but shows a systems issue at a higher level. To improve LS identification, reflex screening and genetic referrals are paramount. In our study, 59% of patients with germline testing had a PV, however 65% of those meeting criteria were never referred, which could reflect a proportion of patients with LS going unidentified. This validates the 2022 NCCN guidelines recommending genetic testing for all CRCs despite age or MSI/MMR status. By removing the barrier of MMR testing, more genetic testing will likely be done. [Table: see text]
Relevance and accuracy of ChatGPT-generated NGS reports with treatment recommendations for oncogene-driven NSCLC.
Authors: Zac Hamilton, Noor Naffakh, Natalie Marie Reizine, Frank Weinberg, Shikha Jain, Vijayakrishna K. Gadi, Christopher Bun, Ryan Huu-Tuan Nguyen
Journal: Journal of Clinical Oncology (2023)

1555 Background: Next-generation sequencing (NGS) is a routine clinical practice in advanced NSCLC. NGS reports are information-dense and clinical interpretation remains a challenge. ChatGPT is a large language model (LLM) AI chatbot that can generate text in response to user-generated prompts. We sought to assess the clinical relevance and accuracy of ChatGPT-generated NGS reports with first-line (1L) treatment recommendations for NSCLC patients with targetable driver oncogenes. Methods: Eight driver oncogenes with FDA-approved targeted treatment for 1L stage IV NSCLC were identified in the latest NCCN Clinical Practice Guidelines available to the AI model (version 5, September 2021). The prompt, “Create a next-generation sequencing report with a list of first-line treatment options for a patient with stage IV non-small cell lung cancer with an [oncogenic driver].” was run in a separate “new chat” 10 times for each driver oncogene (n=80). Each ChatGPT output was recorded and scored. The Relevance Score (RS) awarded 1 point for every NCCN preferred option and 0.5 points for each “other recommended” treatment listed in the AI-generated output, divided by the maximum possible score for the driver oncogene. Spurious recommendations were awarded 0 points. The Accuracy Score (AS) represents reported treatment options listed in NCCN over the total number of treatments in a report. Percentage of reports listing an NCCN-preferred 1L therapy, a clinical trial as an option, and character and word count were also captured. Results: The average length of the AI-generated NGS reports was 117 words (range: 44 – 232). The median number of treatments recommended was 5 (range: 3 – 8). An oncogenic driver-specific preferred 1L treatment was included in 55 reports (68.8%), and a recommendation to explore clinical trials was listed in 43 reports (53.8%). The RS for the total sample was 0.59 (95% CI: 0.52 – 0.65), and the AS was 46.0% (95% CI: 40.2% – 51.8%). Conclusions: ChatGPT can rapidly generate concise NGS reports with treatment options for NSCLC with driver oncogenes. Recommendation relevance was moderate, and accuracy was limited with high variability across oncogenes. Overall, ChatGPT recommendations were promising given the complexity of the task with no prompting or training provided to the AI. As LLM AI platforms mature, they may generate more relevant and accurate NGS reports, offering a potentially valuable tool for NGS report annotation for clinicians, and increased accessibility for patients.[Table: see text]
Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome.
Authors: Ranit Aharonov, Gal Dinstag, Eldad Shulman, Efrat Elis, Doreen Ben-Zvi, Omer Tirosh, Eden Maimon, Sanju SInha, Nishanth Ulhas Nair, Andrea B. Apolo, Stanley Lipkowitz, Raanan Berger, Razelle Kurzrock, Antonios Papanicolau-Sengos, Fatima Karzai, Padma Sheila Rajagopal, Mark R. Gilbert, Kenneth D. Aldape, Tuvik Beker, Eytan Ruppin
Journal: Journal of Clinical Oncology (2023)

1553 Background: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient’s response to a variety of therapies in multiple cancer types, importantly, without training on previous treatment response data. Consequently, in addition to its ability to predict patients' response to approved and well-studied therapies, ENLIGHT can predict the response to new treatments in early development, even before clinical data has accumulated. Accordingly, we study ENLIGHT in two translationally relevant scenarios: Personalized Oncology (PO), aimed at prioritizing approved treatments to a given patient, and Clinical Trial Design (CTD), selecting the subset of most likely responders in a patient cohort. Results: Evaluating ENLIGHT’s performance on 21 blinded clinical trial datasets spanning 11 indications and 15 different drugs in the PO setting, we show that it can effectively predict a patient’s treatment response across multiple therapies and cancer types, with an overall odds ratio of 2.59 ( p=3.41e-8), and a 36% increase in response rate over the baseline ( p=3.30e-13). Its prediction accuracy is better than other state-of-the-art transcriptomics-based signatures. Unlike most signatures that are prognostic or provide insights for only very few, specific treatments, ENLIGHT provides matching scores to a broad range of treatments. Quite strikingly, its performance is comparable to that of supervised predictors developed for specific indications and drugs. In combination with the IFN-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, our results show that by excluding non-responders ENLIGHT can enhance clinical trial success for immunotherapies and other monoclonal antibodies, achieving &gt; 90% of the response rate attainable under an optimal exclusion strategy. Conclusions: ENLIGHT is a powerful transcriptomics-based precision oncology pipeline developed by Pangea Biomed that broadly predicts response to both extant and novel targeted and immune therapies, going beyond context-specific biomarkers.